380 Future Directions
et al. 2002).In vitrostudies have shown that
doxycycline inhibits the degradation of type XI
collagen in articular cartilage, results in lower
levels of active collagenase and gelatinase, and
can inhibit mRNA for inducible nitric oxide
synthase (iNOS) (Yuet al. 1991; Aminet al. 1996;
Smithet al. 1996; Lotz 1999; Fajardo & Di Cesare
2005); NOS is an enzyme responsible for the
secretion of MMPs by chondrocytes.In vivo,
doxycycline reduces cartilage gelatinase and
collagenase in human beings and dogs with
OA, and reduces the incidence and progression
of joint pathology in a canine model of OA
(Yuet al. 1992; Smithet al. 1998; Brandtet al.
2005). The potential for doxycycline to act as
a disease-modifying therapy for human OA
has, consequently, been of substantial interest.
A 2012 Cochrane Review examined the effects
of doxycycline compared with placebo or no
intervention on pain and function in people
with knee or hip OA. The overall conclusion of
this review was that the symptomatic benefit
of doxycycline was minimal to non-existent,
although there was moderate evidence that
doxycycline had a beneficial effect on outcome
measures evaluated, specifically changes in
joint space width over time (da Costa et al.
2012). Two studies have been performed
in veterinary medicine evaluating the use
of doxycycline in canine CR patients. A study
undertaken by Muiret al. 2011 evaluated the use
of oral doxycycline (5 mg kg–1twice daily for
10 weeks) in combination with intra-articular
hyaluronic acid (20 mg per stifle) in 16 dogs
with unilateral CR and a stable contralateral
stifle with radiographic evidence of incipient
CR; the intra-articular hyaluronic acid was
delivered into both stifles after stabilization
surgery was undertaken on the unstable stifle.
This study compared the rate of contralateral
rupture between the 16 treated dogs and 171
dogs also treated for unilateral CR that did not
have hyaluronic acid or doxycycline adminis-
tered postoperatively. The rate of contralateral
rupture was not found to be different between
treated and non-treated dogs (Muiret al. 2011a).
Another prospective trial (von Pfleilet al. 2015)
included 32 client-owned dogs with unilateral
CR that underwent treatment with oral doxycy-
cline (7.5 mg kg–1twice daily for 6 weeks) after
stabilization surgery; radiographic evidence
of incipient contralateral CR was not provided
in this study. The rate of contralateral CR in
dogs treated with doxycycline was compared
to a group of 37 dogs that also underwent
unilateral stifle stabilization surgery but were
not administered doxycycline after surgery.
The results showed that use of doxycycline
did not affect rate of contralateral rupture, or
time to contralateral rupture (von Pfeil 2015).
It is important to note that while these studies
showed that systemic doxycycline did not
influence clinical outcome in dogs with CR,
collectively there were important limitations to
both studies. In the study of Muiret al. (2011a)
there was a small sample size which conse-
quently limited statistical power, while von
Pfeilet al. (2015) did not evaluate dogs for radio-
graphic evidence of incipient contralateral CR
at trial entry. The therapeutic potential of doxy-
cycline continues to be evaluated in laboratory
animal models of OA, focusing specifically on
local intra-articular delivery through hydrogels
or microspheres as a means to limit cartilage
and inflammation in OA-affected joints (Lu
et al. 2013; Aydinet al. 2015).T-cell inhibitors
There are many similarities between inflamma-
tory arthritis associated with CR in the dog and
the inflammatory features of diseases such as
rheumatoid arthritis in human beings. There-
fore, several disease-modifying drugs used for
the treatment of rheumatoid arthritis may be
of benefit in dogs with stifle synovitis associ-
ated with CR. One potential therapy is lefluno-
mide, an immunomodulating drug used for
the treatment of immune-mediated disease in
human beings (Barlettet al. 1991; Marder &
McCune 2007) and dogs (Viviano 2013), includ-
ing immune-mediated polyarthritis (Colopy
et al. 2010). Leflunomide is an effective disease-
modifying drug for rheumatoid arthritis in
human beings (Meieret al. 2013), decreasing
symptoms, radiographic progression, and sys-
temiclevelsofMMPsandpro-inflammatory
cytokines (Litinsky et al. 2006; Marder &
McCune 2007). The active metabolite of lefluno-
mide, A77-1726, is a malononitriloamide analog
that inhibits T- and B-cell proliferation, sup-
presses immunoglobulin production, and inter-
feres with leukocyte adhesion and diapedesis.
Currently, there are no available data evaluating
the use of leflunomide as a disease-modifying